Treatment of inflammation with salicylic acids

ABSTRACT

NEW SUBSTITUTED PHENOXYSALICYLIC ACIDS AND NON-TOXIC PHARMACEUTICALLY ACCEPTABLE SALTS, ESTERS, AND AMIDES DERIVED THEREFROM. THE SUBSTITUTED PHENOXYSALICYLIC ACIDS DISCLOSED HEREIN HAVE ANTI-INFLAMMATORY, ANTI-PYRETIC, AND ANALGESIC ACTIVITY. ALSO INCLUDED ARE METHODS FOR PREPARING SAID PHENOXYSALICYLIC ACID COMPOUNDS.

UniteclStates Patent O 3,646,200 TREATMENT OF INFLAMMATION WITHSALICYLIC ACIDS Tsung-Ying Shen, Bruce E. Witzel, and Gordon L. Walford,Westfield, N.J., assignors to Merck & Co., Inc., Rahway, NJ. No Drawing.Filed June 25, 1969, Ser. No. 836,640

. Int. Cl. A61k 27/00 US. Cl. 424-230 4 Claims ABSTRACT THE DISCLOSURENew substituted phenoxysalicylic acids and non-toxic pharmaceuticallyacceptable salts, esters, and amides derived therefrom. The substitutedphenoxysalicylic acids disclosed herein have anti-inflammatory,anti-pyretic, and analgesic activity. Also included are methods forpreparing said phenoxysalicylic acid compounds.

BACKGROUND OF THE INVENTION The development of anti-inflammatorycompounds in the past two decades has seen the growth of a great manynew drugs. Most of these have been steroids of the ll-oxygenatedpregnane series. These, while highly effective, have the drawback ofcausing many side effects. There is a need in the market for equallyeffective compounds of much simpler structure and having less sideeffects.

SUMMARY OF THE INVENTION Generally, this invention relates to newsubstituted phenoxysalicylic acid compounds and processes for producingthe same. These compounds are useful in that they have anti-inflammatoryactivity and are effective in the prevention and inhibition of edema andgranuloma tissue formation. In addition, some of them have a usefuldegree of anti-pyretic and analgesic activity.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to newsubstituted phenoXysalicylic acids and processes for producing the same.More specifically, this invention relates to substitutedphenoxysalicylic acids, esters, amides, anhydrides and non-toxicpharmaceutically acceptable salts thereof. Still more specifically, thisinvention relates to compounds having the following general formula:

if C-R G g;

O R 45) R3 2 wherein:

ice

R may be hydrogen, acyl (preferably loweracyl such as formyl, acetyl,propionyl, butyryl, etc.), alkyl (preferably loweralkyl such as methyl,ethyl, propyl, isopropyl, butyl, pentyl, etc.), or alkoxycarbonyl(preferably loweralkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,etc.);

R may be hydrogen, halogen (such as chloro, bromo, fluoro, or iodo,preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl suchas trifluoromethyl, etc.), alkyl (preferably loweralkyl, such as methyl,ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl etc.), or alkoxy(preferably loweralkoxy such as methoxy, ethoxy, isopropoxy or butoxy);and

X may be hydrogen, alkyl (preferably loweralkyl, such as methyl, ethyl,propyl, isopropyl, butyl, pentyl, etc.), hydroxy, alkoxy (preferablyloweral'koxy such as methoxy, acetoxy, isopropoxy or butoxy), acyloxy(such as benzoyloxy, acetoxy or propionoxy etc.), halogen (such aschloro, bromo, fluoro or iodo, preferably fluoro or chloro), haloalkyl(preferably haloloweralkyl such as trifluoromethyl, etc.), nitro, amino,alkylamino (preferably loweralkylamino such as methylamino, propylamino,pentylamino, etc.), diloweralkylamino (dimethylamino, dibutylamino,propylpentylarnino, etc.), acylamino (preferably loweracylamino such asformylamino, acetylamino, propionylamino, butyrylamino, etc.), mercapto,alkylmercapto (preferably loweralkylmercapto such as methylmercapto,ethylrnercapto, etc.), alkylsulfinyl (preferably loweralkylsulfonyl suchas methylsulfonyl, ethylsulfonyl, butylsulfinyl, etc.), alkylsulfonyl(preferably loweralkylsulfonyl such as methylsulfonyl, ethylsulfonyl,butylsulfonyl, etc.), sulfonamido, sulfonylamido, alkylaminoalkyl(preferably loweralkylaminoloweralkyl such as methylaminomethyl,ethylaminomethyl, etc.), hydroXyalkyl (preferably hydroxyloweralkyl suchas hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.), alkoxyalkyl(preferably loweralkoxyloweralkyl such as methoxymethyl, methoxyethyl,ethoxyethyl, ethoxypropyl, etc.), mercaptoalkyl (preferablymercaptoloweralkyl such as mercaptomethyl, mercaptoethyl, etc.),alkylmercaptoal-kyl (preferably loweralkylmercaptoloweralkyl such asmethylmercaptomethyl, ethylmercaptoethyl, ethylmercaptopropyl, etc.),cyano, carboxy, carboalkoxy (carbomethoxy, carboethoxy, etc.),carbamoyl, aryl (such as phenyl, tolyl, salicyl), aralkyl such asbenzyl, aryloxy or aralkoxy; provided that the 0R group is always orthoto the II OR group.

Representative compounds of this invention are:

4-(p,0, or m-fluorophenoxy)-salicyclic acid;

5-(p,o, or m-fluorophenoxy)-salicyclic acid;

4-(p,o, or m-trifluorornethylphenoxy)-salicyclic acid; and 5-(p,o, orm-trifluoromethylphenoxy)-salicyclic acid.

This invention also relates to a method of treating inflammation inpatients (animal or human) using a compound of Formula I, particularlyan especially preferred compound as the active constituent.

The compounds of the instant invention can be used to treat inflammationby reducing inflammation and relieving pain in such diseases asrheumatoid arthritis, osteoarthritis, gout, infectious arthritis andrheumatic fever.

The compounds of Formula I also have antipyretic and analgesic activityand Would be administered and used in the same manner and in the samedosage ranges as if they were being used to treat inflammation asdiscussed further on.

The treatment of inflammation in accordance with the method of thepresent invention is accomplished by orally, rectally, parenterally, ortopically administering to patients a composition of a compound of thisinvention particularly the especially preferred compounds in a nontoxicpharmaceutically acceptable carrier, preferably in tablet or capsuleform.

The non-toxic pharmaceutical carrier may be, for example, either a solidor a liquid. Exemplary of solid carriers are lactose, corn starch,gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba,sucrose, agar, pectin, Cabo-sil, and acacia. Exemplary of liquidcarriers are peanut oil, olive oil, sesame oil and water. Similarly, thecarrier or diluent may include a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositionscan be used. For example, if a solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelatin capsule, asyrup or a liquid suspension. Suppositories for rectal administrationand gels for topical administration may be prepared in a conventionalmanner.

The active compounds of Formula I and of the compositions of thisinvention are present in an amount sufficient to treat inflammation,that is to reduce inflammation. Advantageously, the composition willcontain the active ingredient, namely, the compounds of Formula I in anamount of from about 1 mg. to 100 mg. per kg. body weight per day (50mg. to 7 g. per patient per day), preferably from about 2 mg. to 50mg./kg. body weight per day (100 mg. to 3 g. per patient per day).

The method of treatment of this invention comprises internallyadministering to a patient (animal or human), a compound of Formula I,particularly an especially preferred compound admixed with a non-toxicpharmaceutical carrier such as exemplified above. The compounds ofFormula and particularly the especially preferred compounds will beadministered in an amount of from 1 mg. to 100 mg./kg. body weight perday, preferably from about 2 mg. to about 50 mg. per kilogram bodyweight per day and especially from 4 mg. to 20 rug/kg. body weight perday. The most rapid and effective anti-inflammatory efiect is obtainedfrom oral administration of a daily dosage of from about 4 to 20mg./kg./ day. It should be understood, however, that although preferreddosage ranges are given, the dose level for any particular patientdepends upon the activity of the specific compound employed. Also manyother factors that modify the actions of drugs will be taken intoaccount by those skilled in the art in the therapeutic use of medicinalagents, particularly those of Formula I, for example, age, body weight,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination, reaction sensitivities and severity of theparticular disease.

The acid compounds of the invention may be prepared by reacting asubstituted anisole with a substituted phenol to form a phenoxyanisole.The phenoxyanisole is is then demethylated in a conventional manner toform a phenoxyphenol which is carboxylated in a conventional manner toform a phenoxy salicyclic acid, as for example, by heating theappropriate substituted phenoxyphenol under pressure with carbon dioxidegas. The product can then be isolated from the reaction mixture bymethods known in the art. The temperature at which the carboxylationreaction can take place is from 50 to 300 C. The reaction can also takeplace at from atmospheric pressure to high pressure, preferably howeverat 200 C. and about 1600 p.s.i. pressure.

The compounds of this invention wherein R is a group such that an esteris the final compound (i.e. R is alkoxy) are prepared by anyesterification procedure using an esterifying agent containing theappropriate R group. For example, the carboxylic acid compounds of thisinvention 4 may be reacted with the appropriate loweralkanol,(preferably methanol) at elevated temperatures in the presence of astrong acid such as hydrochloric acid, sulfuric acid, p-toluene-sulfonicacid and the like to form the desired ester.

The compounds of this invention wherein .R is a group such that an amideis the final compound (i.e. R is amino) may be prepared by any suitableamidation reaction. For example, the carboxylic acid compound(preferably the methyl or ethyl ester) may be reacted with ammonia,ammonium hydroxide, or an amine compound, at any suitable temperature(room temperature to reflux). When the amino group is desired, it ispreferred to carry out the reaction with ammonia in a bomb attemperatures about C. to form the desired R (amino) compound.Preferably, when an amide is desired which is derived from an aminoacid, the following reaction sequence is followed: The carboxylic acidfinal compound is reacted with isobutyl chlorocarbonate to form themixed anhydride. This compound is in turn reacted with the desired aminoacid ester and subsequently hydrolyzed to form the desired amide.

The salts of the final acid compounds of this invention may be preparedby any of the well-known metathesis procedures. For example, thecarboxylic acid compound may be reacted with an inorganic base such assodium hydroxide, potassium hydroxide, ammonium hydroxide and bariumhydroxide and the like. The anhydride of this invention may be preparedby any of the well-known procedures in the art.

The final compound, wherein R is lower alkyl (preferably methyl), may beprepared by any appropriate alkylation reaction. For example, thecorresponding hydroxy benzoic acid, ester, or amide (preferably theester), may be reacted with a di(lower al'kyl)sulfate (preferablydimethyl sulfate) in the presence of a base (such as an alkalicarbonate) at any suitable temperature (room temperature to reflux butpreferably at or near reflux) with subsequent acidification of thereaction mixture, such as with hydrochloric acid, sulfuric acid, and thelike, to form the desired R compound.

The following examples are presented to further illustrate theinvention:

EXAMPLE 1 The preparation of 5-(p-chlorophenoxy)- salicylic acid EXAMPLE2 The preparation of 3-chloro-4-phenoxyphenol To a stirred mixture ofwater (300 ml.) and concentrated sulfuric acid (30 ml.) is added3-chloro-4- phenoxyaniline (0.3 m.) in small portions. The resultantmixture is then cooled to less than 10 C. by the addition of crushed ice(250 g.) plus any external cooling needed, A solution of sodium nitrite(22 g.) in water (100 ml.) is added portion-wise so that the temperaturestays below 10 C., the mixture allowed to warm 'to room temperature,heated gently until evolution of nitrogen is completed, and the mixturecooled. Extraction of the mixture with chloroform, followed bychromatography of the extracts on a silica gel column using'anether-petroleum ether system (v./v. 0-50% ether) as eluant yields3-chloro-4-phenoxyphenol.

When p-(2-chlorophenoxy)aniline, p (2,4-dichlorophenoxy)-aniline,p-(4-chlorophenoxy)-m-chloroaniline, p- (2-chlorophenoxy)-m-chloroaniline, p,- (2,4,6-trichlorophenoxy) aniline,p-(3,4-dimethylphenoxy)=ani1ine, p

(4-chloro-3,5-dimethylphenoxy)aniline, or p-(4-carboxyphenoxy)-anilineis used in place of 3-chloro-4-phenoxyaniline in the above example, thecorresponding phenol, p-(2-chlorophenoxy) phenol,p-(2,4-dichlorophenoxy)- phenol, p-(4-chlorophenoxy)m-chlorophenol,p-(2-chlorophenoxy) m-chlorophenol, p- 2,4,6-trichlorophenoxy phenol, p-(3,4-dimethylphenoxy phenol, p- (4-chloro-3 5-dimethylphenoxy)-phenol orp-(4-carboxyphenoxy) phenol (purified via the methyl ester) is obtained.

EXAMPLE 3 The preparation of 4-(p-methylphenoxy)-anisole A mixture ofp-bromoanisole (0.15 m.), p-cresol (0.18 m.), powdered anhydrouspotassium carbonate (6.9 g.) and copper bronze (0.2 g.) is heated at 210C, for two hours, cooled, excess alkali added, the mixture extractedwell with ether and benzene, the combined extracts dried well overanhydrous magnesium sulfate, filtered and concentrated. Distillationunder reduced pressure, or chromatography on a silica gel column of theresidue obtained, using an ether-petroleum ether system as eluant yields4-(p-methylphenoxy)anisole.

When o-cresol, m-cresol, m-, or p-nitrophenol, mor p-phenylphenol,4-hydroxydiphenylmethane, 4-hydroxydiphenylether, 4-hydroxyacetophenone,o-, m-, and p-chlorophenol or o-, mand p-fluorophenol are used in placeof p-cresol in the above example, 4-(0- and mmethylphenoxy)-anisole,4-(0, m and p-nitrophenoxy)- anisole, 4-(mand p-phenylphenoxy)-anisole,4-(p-benzylphenoxy)-anisole, 4- (pphenoxyphenoxy-anisole, 4-(pacetylphenoxy)-anisole, 4-(o-, mand p-chlorophenoxy)- anisole and4-(o-, mand p-fiuorophenoxy)-anisole are obtained, respectively.

When rn-bromoanisole is used in place of p-bromoanisole in the aboveexample, and reacted with all the phenols listed, the corresponding3-(substituted phenoxy)-anisoles are obtained.

EXAMPLE 4 The preparation of 4-(p-methylphenoxy)phenol A mixture of4-(p-methylphenoxy)anisole (5 g.) and pyridine hydrochloride (125 g.)under a dry nitrogen atmosphere is placed in an oil-bath set at 230 C.,kept there minutes, removed from the bath, cooled, and extracted withether. The ether extracts are washed with water, dried, and the residueobtained upon removal of the ether chromatographed on a silica gelcolumn using an ether-petroleum ether (v./v. 070% ether) system yielding4- (p-methylphenoxy -phenol.

Other standard methods of demethylation, such as acetic acid-hydrogenhalide, aluminum chloride-benzene, potassium hydroxide-ethylene glycol,etc., may also be used.

When the substituted anisoles of Example 3 are used in place of4-(p-methylphenoxy)anisole in the above example, there is obtained 4-(0-and m-methylphenoxy)- phenols, 4-(o-, m-, and p-nitrophenoxy)-phenols,4-(mand p-phenylphenoxy)phenols, 4-(p benzylphenoxy)- phenol,4-(p-phenoxyphenoxy)phenol, 4-(p acetylphenoxy)-phenol, 4 (o-, m-, andp-chlorophenoxy)phenols, 4-(o-, mand p-fiuorophenoxy)-phenols, 3-(o-,111-, and p-methylphenoxy)phenols, 3-(o-, m-, andp-nitrophenoxy)-phenols, 3-(mand p-phenylphenoxy)phenols, 3-(p-benzylphenoxy) phenol, 3 (p phenoxyphenoxy)- phenol,3-(p-acetylphenoxy)phenol, 3-(o-, m-, and pchlorophenoxy)-phenols and3-(o-, m-, and p-fluorophenoxy)-phenols, respectively.

EXAMPLE 5 When the phenols from Example 4 are used in place of4-(p-chlorophenoxy)phenol in Example 1, there are obtained 5-(o-, m-,and p-methylp-henoxy)salicylic acids, 5-(o-, mandp-nitrophenoxy)salicylic acids, S-(mand p-phenylphenoxy)salicylic acids,S-(p benzylphenoxy)- salicylic acid, S-(p-phenoxy-phenoxy)salicylicacid, S-(pacetylphenoxy)-salicylic acid, 5-(oandm-chlorophenoxy)salicylic acids, 5-(o-, mand p-fiuorophenoxy)-salicyclicacids, 4-(o-, mand p-methylphenoxy)salicylic acids, 4-(o-, m-, andp-nitrophenoxy)salicylic acids, 4- (mand p-phenylphenoxy)salicylicacids, 4-(p-benzyl phenoxy)-salicylic acid, 4-(p-phenoxyphenoxy)salicylic acid, 4-(p-acetylphenoxy)salicylic acid, 4-(o-, mandpchlorophenoxy)-salicylic acids, and 4-(o-, mandpfiuorophenoxy)-salicylic acids.

When the phenols from Example 2 are used above, there are obtained4-chloro-5-phenoxy-salicylic acid, 5- (o-chlorophenoxy)salicylic acid(prepared above also), 5-(2,4-dichlorophenoxy)salicylic acid, 4-cholro 5(pchlorophenoxy)-salicylic acid, 4-chloro-5-(o chlorophenoxy)-salicylicacid, 5-(2,4,6-trichlorophenoxy)-salicylic acid,5-(3,4-dimethylphenoxy)salicylic acid, 5-(4-chloro-3,5-dimethylphenoxy)salicylic acid, and 5 (p carboxyphenoxy)-salicylicacid, respectively.

EXAMPLE 6 The preparation of Z-acetoxy-S-(p-chlorophenoxy)- 'benzoicacid To a mixture of 5-(p-chlorophenoxy)-salicylic acid (0.04 ml.) inanhydrous pyridine (15 ml.) is added acetic anhydride (28 ml.) and theresultant mixture heated on the steam cone for 1.5 hours. The mixture iskept free from moisture during this time. On cooling, the mixture isadded to a stirred 500 m1. portion of water, the aqueous systemextracted well with chloroform, the chloroform extracts washed with 1 Nhydrochloric acid, water, and then dried over anhydrous magnesiumsulfate. Concentration of the filtered solution yields2-acetoxy-5-(pchlorophenoxy) benzoic acid.

When propionic or butyric anhydride is used in place of acetic anhydridein the above example, the corresponding propionoxy or butyroxy compoundis obtained.

When the salicylic acids of Example 5 are used in place ofS-(p-chlorophenoxy)salicylic acid, above, the corresponding acyloxybenzoic acids are obtained.

EXAMPLE 7 The preparation of methyl 5-(p-chlorophenoxy)- salicylate To asolution of anhydrous methanol ml.) containing 0.2 g. of anhydroushydrogen chloride (or one small drop of concentrated sulfuric acid) isadded S-(pchlorophenoxy)-salicylic acid and the resultant mixture heatedunder reflux for three hours. The solvent is removed in vacuo, theresidual material partitioned between chloroform-dilute sodiumbicarbonate solution, and the layers separated. The chloroform layer isdried, filtered, and concentrated in vacuo to leave methylS-(pchlorophenoxy) -salicylate.

When ethanol is used in place of methanol in the above reaction, thecorresponding ethyl ester is obtained.

When the salicylic acids of Example 5 are used in place of5-(p-chlorophenoxy)salicylic acid in the above example, thecorresponding methyl and ethyl esters are obtained.

Esterification is also achieved using diazomethane in methylene chloridesolution.

EXAMPLE 8 The preparation of phenyl S-(p-chloropheno-xy)salicylate To amixture of polyphosphate esters (l5 equiv.) in chloroform is added oneequivalent each of 5-(p-chl0rophenoxy)-salicylic acid and phenol, andtheresultant mixture heated gently for 30 minutes. The chloroform mixtureis cooled, washed with dilute bicarbonate solution, the chloroform layerdried, filtered and evaporated in vacuo to yield phenylS-(p-chlorophenoxy)salicylate.

When the salicylic acids of Example 5 are used in place ofS-(p-chlorophenoxy)salicylic acid in the above reaction, thecorresponding phenyl esters are obtained.

7 EXAMPLE 9 The preparation of methyl S-(p-aminophenoxy)-salicylate Amixture of methyl S-(p-nitrophenoxy)-salicylate (0.01 ml.) inmethanol-dioxane (1:1) (200 ml.) is reacted with hydrogen at roomtemperature, 40 p.s.i., in the presence of 10% palladium on carbon 0.3g.). The mixture is filtered, the cake Washed well with methanol, thefiltrate evaporated in vacuo, the residue chromatographed on a silicagel column using a methanol-methylene chloride system as eluant (v./v.30% methanol) to yield methyl (p-aminophenoxy)-salicylate.

EXAMPLE The preparation of methyl S-(p-dimethylaminophenoxy) -salicylateA mixture of methyl 5-(p-nitrophenoxy)salicylate (0.012 m.), methanol(150 ml.), glacial acetic acid (2 ml.), 37% formaldehyde (4 ml.) andRaney nickel (0.5 teaspoonful) is treated with hydrogen (40 psi.) atroom temperatrue. When hydrogen uptake is complete, the mixture isfiltered, the cake washed with fresh methanol, filtered and thefiltrates combined. The mixture is then partitioned betweenchloroform-dilute sodium bicarbonate solution, the layers separated, theaqueous solution extracted with fresh chloroform and then with ether,the organic layers combined, dried, filtered, and concentrated.Chromatography of the residue on a silica gel column using anether-petroleum ether (v./v. 0-100 %ether( system yields methyl5-(p-dimethylaminophenoxy)-salicylate.

EXAMPLE 11 The preparation of methyl 5-(p-cyanophenoxy) salicylate Amixture of methyl 5-(p-chlorophenoxy)-salicylate (0.02 m.), cuprouscyanide (0.03 m.), and N-methylpyrrolidone is de-aerated, covered with anitrogen atmosphere and heated slowly to 180 C., kept at thistemperature for 3 hours, allowed to cool, partitioned between benzene-7%hydrochloric acid containing ferric chloride (0.03 m.), the benzenelayer separated, dried, concentrated and the residue chromatographed ona silica gel column using an ether-petroleum ether system as eluant(v./v. S50% ether) to yield methyl 5-(pcyanophenoxy)- salicylate.

EXAMPLE 12 The preparation of S-(p-carbarnylphenoxy) salicyclic acid Amixture of 5-(p-cyanophenoxy)-salicylic acid (0.002 m.) andpolyphosphoric acid (5 ml.) is heated on a steam cone for one hour,cooled, added to water, the aqueous layer basified with sodiumbicarbonate, heated on the steam cone to hydrolyze any ester oranhydride formed, filtered and acidified with dilute hydrochloric acid.The 5- (p-carbamylphenoxy)-salicylic acid is then collected.

EXAMPLE 13 The preparation of methyl S-(p-carbomethoxyphenoxy-salicylate When S-(p-carboxyphenoxy)-salicylic acid is esterified asper the conditions of Example 7, there is obtained methylS-(p-carbomethoxyphenoxy)-salicylate.

EXAMPLE 14 The preparation of methyl S-(p-benzyloxyphenoxy -o-anisateWhen p-benzyloxyphenol and methyl S-bromo-o-anisate are used in place ofp-cresol and p-bromoanisole, respectively, in Example 3, methylS-(p-benzyloxyphenoxy)-oanisate is obtained.

8. EXAMPLE 15 The preparation of methyl S-(p-hydroxyphenoxy -o-anisate Amixture of methyl 5-(p-benzyloxyphenoxy)-o-anisate (0.01 m.), methanol(200 ml.) and 10% palladium on carbon (0.2 g.) is reacted in a hydrogenatmosphere (40 psi.) at room temperature. When the theoretical amount ofhydrogen has been absorbed, the mixture is filtered and the solventremoved in vacuo to yield methyl 5- (p-hydroxyphenoxy)-o-anisate.

EXAMPLE 16 The preparation of methyl S-(p-hydroxyphenoxy) salicylic acidWhen either of the compounds of Example 15 is reacted with pyridinehydrochloride as per Example 4, methyl S-(p-hydroxyphenoxy)-salicylicacid is obtained.

EXAMPLE 17 The preparation of 2-acetoxy-5-(p-acetoxyphenoxy)- benzoicacid EXAMPLE 18 The preparation of p-(4-acetoxyphenoxy) benzotrifluorideA stainless steel lined shaker is charged withp-(pacet0xyphenoxy)-benzoic acid (0.02 in.) under a nitrogen atmosphere,the system cooled to Dry-Ice temperatures, and sulfur tetrafiuoride (0.1m.) condensed into the tube. The mixture is then heated at C. for eighthours, cooled, vented, the residual material taken up in ether,filtered, and concentrated. The material thus. obtained is thenchromatographed on a silica gel column using an ether-petroleum ether(v./v. 030% ether) system as eluant, yieldingp-(4-acetoxyphenoxy)benzotrifluoride.

Gentle heating of this material in a methanolic solution with either anacid or basic catalyst, followed by ether extraction of the diluted(water) mixture yields p-(p-hydroxyphenoxy)-benzotrifluoride.

EXAMPLE 19 The preparation of 5-(p-trifluoromethylphenoxy)-' salicylicacid When p-(p-hydroxyphenoxy)-benzotrifiuoride is used in place ofp-(4-chlorophenoxy)-phenol in Example 1, there is obtained5-(p-trifluoromethylphenoxy)-salicylic acid.

EXAMPLE 20 The preparation of S-(p-methoxyphenoxy)-o-anisic acid Thepreparation of 4-hydroxy-4'-mercaptodiphenyl ether Whenp-methylmercaptophenol is used in place of pchlorophenol in Example 1,and the resultant p-(4-methylthiophenoxy)-anisoe demethylated withpyridine hydrochloride as per Example 4, 4 hydroxy-4-mercaptodiphenylether is obtained.

EXAMPLE 22 The preparation of p-(4-methylmercaptophenoxy)-phenol Amixture of 4-hydroxy 4' mercaptodiphenyl ether (0.01 m.) in a de-aeratedaqueous potassium hydroxide solution (0.01 m.) is treated withdimethylsulfate (0.012 m.) at room temperature over one hour, themixture acidified, extracted well with ether, and the dried extractschromatographed on a silica gel column using an ether-petroleum ethersystem (v./v. -30% ether) as eluant yielding ap-(4-methylmercaptophenoxy)-phenol.

EXAMPLE 23 The preparation of -(p-methylmercaptophenoxy)- salicylic acidWhen p-(4-methylmercaptophenoxy)-phenol is used in place ofp-(4-chlorophenoxy)-phenol in Example 5, 5-(p-methylmercaptophenoxy)-salicylic acid is obtained.

EXAMPLE 24 The preparation of 5-(p-mercaptophenoxy)-salicylic acid Whenthe salicylic acid from Example 23 is used in place of methylS-(p-hydroxyphenoxy)-o-anisate in Example 16, there is obtained 5(p-mercaptophenoxy)- salicylic acid.

EXAMPLE 25 The preparation of 5-(p-methylsulfinylphenoxy)- salicylicacid To a cooled solution of S-(p-methylthiophenoxy)-salicylic acid(0.01 m.) in methanol-acetone is added a solution of sodiummetaperiodate (0.01 m.) in a minimum amount of water, and the mixturestirred at or below room temperature until precipitation of sodiumiodate is completed. The iodate is removed by filtration, the solventsremoved in vacuo, and the residue taken up in chloroform and ether, theorganic solvents combined, dried and concentrated. Purification isaffected via column chromatography of the methyl ester, or byrecrystallization of the acid, yielding 5-(p-methylsulfonylphenoxy)-salicylic acid.

EXAMPLE 26 .The preparation of 5-(p-methylsulfonylphenoxy)-salicylicacid When two equivalents of sodium metaperiodate are used in Example25, and a higher temperature employed,

or when the methylmercapto compound is oxidized with peroxide in aceticacid there is obtained S-(p-methylsulfonylphenoxy) salicylic acid.

EXAMPLE 27 The preparation of methyl2-acetoxy-5-(p-bromomethylphenoxy)-benzoate A mixture of methyl5-(p-methylphenoxy)-2-acetoxybenzoate (prepared from the correspondingacid and diazomethane) (0.05 m.), N-bromosuccinirnide (0.05 m.)(purified just before use by pumping out at 0.5 mm. over P 0 carbontetrachloride (500 ml.) and dibenzoyl peroxide (0.002 m.) is refluxedgently for 3 hours, cooled, the succinimide removed by filtration, andthe solvent removed in vacuo to yield methyl2-acetoxy-5-(p-bromomethylphenoxy -benzoate.

EXAMPLE 28 The preparation of methyl 5-(p-hydroxymethylphenoxy)-salicylate A mixture of methyl2-acetoxy-5-(p-bromomethylphenoxy)-benzoate (0.01 m.), silver acetate(0.01 m.) and acetic acid (30 ml.) is heated gently for three hours,

EXAMPLE 29 The preparation of methyl 5-(p-methoxymethylphenoxy)-salicylate Methyl 2 acetoxy 5 (p-bromomethylphenoxy)- benzoate (0.01 m.)is added to a stirred solution of sodium methoxide (0.02 m.) inanhydrous methanol, the mixture refluxed gently for one hour, cooled, atrace of dilute hydrochloric acid added to neutralize the mixture, thesolvents removed in vacuo, and the residue chromatographed on a silicagel column using an ether-petroleum ether system (v./v. 0-40% ether) aseluant to yield methyl 5-(p-methoxymethylphenoxy)-salicylate.

When potassium methylmercaptide is used in place of sodium methoxide,methyl 5-(p-methylthiomethylphenoxy)-salicylate is obtained.

EXAMPLE 30 The preparation of methyl 5-(p-aminomethylphenoxy)-salicylate hydrochloride Methyl S-(p-cyanophenoxy)-salicylate (0.005 m.)in acetic acid (50 ml.) is reduced at room temperature under a 40 psi.hydrogen atmosphere, using 0.2 g. platinum oxide as a catalyst. When thetheoretical amount of hydrogen is consumed, the mixture is filtered, thesolvent removed in vacuo, the residue taken up in a chloroformethermixture, filtered, ethereal-hydrogen chloride added and themethyl-S-(p-aminomethylphenoxy)-silicylate hydrochloride collected.

EXAMPLE 3 l The preparation of methyl 5-(p-dimethylaminophenoxy)-salicylate A mixture of methylS-(p-aminomethylphenoxy)- salicylate (0.004 m.), 37% formaldehyde (6ml.), dried 1,2-dimethoxyethane ml.), glacial acetic acid (50 ml.) andRaney nickel (1 teaspoon) is treated with hydrogen (40 psi.) at roomtemperature. When hydrogen uptake is completed, the mixture is filtered,the cake washed Well with fresh dimethoxyethane, the combined filtratesdistributed between chloroform-dilute sodium bicarbonate solution, thechloroform layer dried, filtered, concentrated, and the residuechromatographed on a silica gel column using an ether-petroleum ethersystem (v./v. 0100% ether) as eluant ethyl 5-(pdimethylaminophenoxy)-salicylate is obtained.

EXAMPLE 32 The preparation of 5-(p-benzyloxyphenoxy)- salicylic acid Amixture of 5-(p-hydroxyphenoxy)-salicylic acid (0.01 m.), anhydrouspotassium carbonate (0.02 m.)

and anhydrous methanol (50 ml.) is stirred for 30 minutes, protected bya calcium chloride drying tube. Benzyl chloride (0.02 m.) is added, themixture refluxed for 6 hours, potassium hydroxide (2 g.) and water ml.)added, the mixture refluxed one hour, filtered cold, acidified withdilute hydrochloric acid, the acid collected and purified viarecrystallization or column chromatography of its methyl ester to yield5-(p-benzyloxyphenoxy)- salicyclic acid.

1 1 EXAMPLE 33 'The preparation of methyl 2-carboxy-4-(p-chlorov.phenoxy) -phenyl carbonate EXAMPLE 34 The preparation of methyl4-methyl-5-phenoxy-salicylate When phenol and methylS-bromo-4-methyl-o-anisate are used in place of p-cresol andp-bromoanisole, respectively, in Example 3, and the resulting methyl4-methyl-S-phenoxy-o-anisate reacted with pyridine hydrochloride as perExample 4, there is obtained methyl 4-methyl-5-phenoxy-salicylate.

EXAMPLE 35 The preparation of Z-bromo-S-methoxybenzotrifiuoride When theacetate of S-hydroxy-Z-bromobenzoic acid is used in place ofp-(4-acetoxyphenoxy)-benzoic acid in Example 18, and the resultantmixture hydrolyzed under mild conditions, there is obtained2-bromo-5-hydroxybenzo trifluoride, which on treatment with diazomethaneyields 2-bromo-5-methoxybenzotrifluoride.

EXAMPLE 36 The preparation of 4-benzyloxy-Z-bromoanisole When3-brorno-4-methoxyphenol is reacted with one equivalent of benzylchloride as per Example 32, there is obtained4-benzyloxy-2-bromoanisole.

EXAMPLE 37 The preparation of 5-methoxy-2-phenoxybenzotrifiuoride and4-benzyloxy-Z-phenoxyanisole When 2-bromo-S-methoxybenzotrifluoride and4-benzyloxy-2-bromoanisole are reacted with phenol as per Example 34,there are obtained 5-methoxy-Z-phenoxybenzotrifiuoride and4-benzyloxy-Z-phenoxyanisole, respectively.

EXAMPLE 38 The preparation of 4-phenoxy-B-trifluoromethylphenol Thepreparation of 5-phenoxy-4-trifiuoromethylsalieylic acid and5-methoxy-4-phenoxysalicylic acid When 4-phenoxy-3-trifluoromethylphenoland 4-methoxy-3-phenoxyphenol are carbonated as per Example 1,

there are obtained 5-phenoxy-4- trifluoromethylsalicylic acid and5-methoxy-4-phenoxysalicylic acid, respectively.

EXAMPLE 41 Thepre paration of 5-(p-chlorobenzoxysalicylanilide mixtureof phenyl 5-(pchlorophenoxy)-salicylate (0.1 m.), aniline (0.1 m.) andl-methylnaphthalene (50 n1l.)-is heated slowly to 230 C., kept at thistemperature .until phenol has stopped distilling, charcoal (2 g.) added,

then 20 ml. additional methylnaphthalene, the mixture 12 heated 10minutes, filtered hot, and cooled. The collected anilide is thenrecrystallized to yieldpure 5-p-chlorophenoxysalicylanilide.

7 EXAMPLE 42 V The preparation of S-(p-chlorophenoxy)-salicylarnide Amixture of methyl 5 (p-chlorophenoxy)-salicy1ate and concentratedammonium hydroxide (five-fold excess) is heated at C., in a sealed tubefor 6 hours. After cooling, water is added and the 5-(p-chlorophenoxy)-salicylamide collected.

When monomethylamine, dimethylamine, ethylarnine, diethylamine,morpholine, piperidine, etc. are used in place of ammonium hydroxide,the corresponding amides are obtained.

EXAMPLE 43 The preparation of N,N-diethylaminoethylS-(p-chlorophenoxy)-salicylate To a mixture of5-(p-chlorophenoxy)-salicyclic acid (0.01 m.) andN,N-diethylethanolamine (0.01 m.) in anhydrous tetrahydrofuran (100 ml.)is added a solution of dicyclohexylcarbodiimide (0.01 m.) in a rninimumof the same solvent. The mixture is stoppered, shaken well, and allowedto stand overnight. The precipitated dicyclohexylurea is removed byfiltration, the filtrate concentrated in vacuo, the residue partitionedbetween ether and 1 N hydrochloric acid, the layers separated, theaqueous layer washed once with fresh ether and neutralized withsaturated sodium bicarbonate solution. Extraction with chloroform,followed by removal of the chloroform in vacuo (high vacuum pump toremove traces of starting amine) yields N,N-diethylaminoethyl 5-(p-chlorophenoxy)salicylate.

EXAMPLE 44 The preparation of sodium 5-(p-chlorophenoxy)- salicylateEXAMPLE 45 V The preparation of the diethylaminoethanol salt of 5-(p-chlorophenoxy)-salicycli'c acid N,N-diethylethanolamine (0.001 m.) inether (5 ml.) is added to a stirred solution of 5-(p-chlorophenoxy)-salicyclic acid (0.001 m.) in chloroform-methanol, the resultant mixtureallowed to stir for one hour, the salt collected or the solvent removedin vacuo to yield the diethylaminoethanol salt of 5(p-chlorophenoxy-salicyclic acid. l

When piperidine, morpholine, triethylamine, N-methylpiperidine,'N-methylmorpholine, tributyl amine or other organic amines are used inplace of diethylethanolamine in the above example, the correspondingsalt is obtained.

We claim:

1. A method of treating inflammation which comprises administering to apatient 1 mg. to 100 mgsper. kg. body weight per day of a compound ofthe formula:

. g o II c a O X (IL-5) @0112 13 14 wherein 4. A method of treatmentaccording to claim 1 wherein X is halogen, haloloweralkyl, loweralkoxyor dilowerthe compound to be administered is 5- (m oro-fiuorophenalkylamino; 0Xy)-sa1icyc1ic acid. R is hydroxy; R i h d 5References Cited R is hydrogen and the pharmaceutically non-toxic acidUNITED STATES PATENTS a idition si g f provlded that the group 183,105,090 9/1963 Leonard 260 520 a ways 6 3,385,886 5/1968 Nicholson eta1. 424-317 E L 10 3,228,831 1/1966 Nicholson et a1. 424317 0 FOREIGNPATENTS group and provided the phenoxy radical is attached 966,4798/1964 Great Britain 260 520 to the 4 or 5-positi0n of the salicyclicacid moiety. 2. A method of treatment according to claim 1 whereinSTANLEY FRIEDMAN Primary E Xaminer the compound to be administered is 5-(p-fluorophenoxy)- 15 salicyclic acid. US

3. A method of treatment according to claim 1 wherein 2 0 52 thecompound to be administered is 4-(p,o or m-fluorophenoxy)-sa1icyclicacid.

UN] :1 STATES PATENT wee CETEFECAT OF CORRECTION Dated February 29, 1972Patent No. 3,646,200

Invent )Tsunq-Yinq Shen; Bguce E. W itzel & Gordon L. Walford It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

T '1 In Column 1, line 59, the word "propylamnio" should be-propylamino-;

In Column 2, line 30, the words "loweralkylsulfonyl"; "methylsulfonyl"and "ethylsulfonyl" should be ---loweralkylsulfinyl-; --methylsulfinyland --ethylsulfinyl-, respectively;

In Column 6, line 25, (0. 04 ml.) should be --(0.04 m.)-;

and

In Column 13, line 10, the formula reading should be Signed and sealedthis 15th day of August 1972.

(SEAL) Attest:

EDWARD MQFLETCHERJR, ROBERT GOTTSGHALK Attesting Officer Commissioner ofPatents

